Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks, and in a variety of other vaso-occlusive disorders. When a blood vessel is damaged, either by acute intervention such as angioplasty, or, more chronically, by the pathophysiological processes of atherosclerosis, platelets are activated to adhere to the disrupted surface and to each other. This activation, adherence and aggregation may lead to occlusive thrombus formation in the lumen of the blood vessel.
Antiplatelet therapy has been used in a wide variety of cardiovascular disease states and in conjunction with interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary angioplasty. Inhibitors of the glycoprotein complex GP IIb/IIIa, including abciximab, tirofiban, and eptifibatide, are used intravenously to inhibit platelet aggregation. Platelet aggregation inhibition results in reduced incidences or reduced severity of adverse events such as death or damage to the heart. Typical use of these inhibitors involves initial bolus injection and subsequent sustained infusion, for a period of hours or days.
Holmes et al., Coronary Artery Disease (2001) 12:245-253, describe the efficacy of platelet aggregation inhibition induced by treatment with tirofiban hydrochloride in patients with unstable angina, non-ST-segment elevation myocardial infarction or symtomatic coronary disease undergoing percutaneous coronary intervention. Patients received either 0.4 xcexcg/kg/min over 30 minutes followed by 0.1 xcexcg/kg/min, or 10 xcexcg/kg bolus injection followed by continuous infusion at 0.15 xcexcg/kg/min.
Neumann, et al., J. Am. Coll. Cardiol. (2001) vol. 37, pp. 1323-1328, describe antiplatelet effects if tirofiban hydrochloride in patients undergoing intracoronary stent placement for symptomatic coronary artery disease. Patients received 10 xcexcg/kg bolus injection followed by continuous infusion at 0.15 xcexcg/kg/min for 72 hours.
Topol et al., N Engl J Med, (2001) vol. 344, pp. 1888-1894, describe the use of tirofiban hydrochloride for the prevention of ischemic events with percutaneous coronary revascularization. Treated patients were those scheduled to undergo a coronary stenting procedure of a newly stenotic or restenotic atherosclerotic lesion in a native vessel or a bypass graft. Patients received 10 xcexcg/kg bolus injection followed by continuous infusion at 0.15 xcexcg/kg/min for 18-24 hours.
Kabbani et al. The American Journal of Cardiology (2002) vol. 89 pp. 647-650, describe the use of tirofiban hydrochloride in patients having an acute coronary syndrome in whom a percutaneous coronary intervention was mandated. Patients received 10 xcexcg/kg bolus injection followed by continuous infusion at 0.15 xcexcg/kg/min for 18-24 hours. Results from the study show that the average inhibition of maximal aggregation during the period of time between 15 and 60 minutes following administration of the bolus dose was between 61% and 66%.
In each of the above studies, patients were treated either with no bolus dose of tirofiban hydrochloride or a 10 xcexcg/kg bolus dose of tirofiban. The duration of continuous infusion was between 18 and 72 hours. In no case was the bolus amount greater than 10 xcexcg/kg.
We have now found that substantially more effective inhibition of platelet aggregation can be obtained by administering, to a patient in need thereof, a bolus dose of tirofiban hydrochloride of about 25 xcexcg/kg. The increased bolus dose greatly improves the overall platelet aggregation inhibitory effect of tirofiban therapy, providing an aggregation inhibition of greater than 90%, without the need to increase the concentration of tirofiban hydrochloride solution delivered during the continuous infusion phase of tirofiban therapy, and without the need to extend the duration of the continuous infusion phase. Further, this benefit is achieved in the absence of increased undesirable side effects.
The invention is a method for inhibiting platelet aggregation in a patient in need thereof, comprising 1) administering to the patient a bolus injection of an active drug, in an amount of about 25 xcexcg/kg, and 2) administering to the patient, after the bolus injection, an intravenous infusion of an active drug for a period of between about 12 hours and about 72 hours, in an amount of about 0.15 xcexcg/kg/min, wherein the active drug is tirofiban or a salt thereof.
In a class of methods of the invention, the salt is tirofiban hydrochloride. In a subclass of the class, the amount of tirofiban hydrochloride in the bolus injection is 25 xcexcg/kg. In another subclass of the class, the intravenous infusion is between 12 hours and 72 hours, e.g. between 18 hours and 72 hours.
The invention is also a method for reducing the risk of acute coronary syndrome in a patient at risk to acute coronary syndrome, comprising 1) administering to the patient a bolus injection of an active drug, in an amount of between about 25 xcexcg/kg, and 2) administering to the patient, after the bolus injection, an intravenous infusion for a period of between about 12 hours and about 72 hours, of the active drug, in an amount of about 0.15 xcexcg/kg/min, wherein the active drug is tirofiban or a salt thereof.